RESEARCH PROPOSAL: The goal of this grant is to define the role of type I plasminogen activator inhibitor (PAI-1) in the development of intimal lesion formation during atherogenesis and following vascular injury. Decreased fibrinolytic activity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. PAI-I is the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. To accomplish this goal, we propose the following specific aims: 1) examine the influence of PAI-1 expression on the development of atherosclerosis in atherosclerotic-prone mice that either overexpress or lack the gene for PAI-1, 2) determine the source of proatherogenic PAI-1 (i.e. plasma vs platelets vs other cell types) 3) determine the role of the PAI-1 interaction with vitronectin on atherogenesis and 4) examine the influence of PAI-1 expression on intimal lesion formation following mechanical arterial injury. CANDIDATE AND ENVIRONMENT: The candidate is in the process of completing a fellowship in Cardiology at the University of Michigan. As part of his fellowship, he spent 3 months participating in a molecular biology course for postdoctoral students and 2 years in the laboratory of David Ginsburg studying issues in coagulation and fibrinolysis. In July of 1997 he plans to join the Cardiology staff and pursue an investigative career with 75% of his time devoted to research. He plans to focus his research program on the role of fibrinolysis in the development of vascular disease under the mentorship of Drs. David Ginsburg and Elizabeth Nabel. The K08 award would provide critical support during this important phase of his scientific training and transition to an independent junior faculty position. Laboratory space is available to him within the Division of Molecular Medicine and Genetics and the Cardiovascular research center. Members of the Divisions of Cardiology and Molecular Medicine and Genetics will provide technical and academic support for this proposal. (End of Abstract)